Incidence and Survival of urothelial carcinoma of the urinary bladder in Norway 1981-2014

Urothelial carcinoma of the urinary bladder (UCB) is the 4th most common cancer type in men in developed countries, and tumor recurrence or progression occurs in more than half of the patients. This article describes the trends of UCB incidence and survival from 1981 to 2014, including both invasive and non-invasive UCB using data from the Cancer Registry of Norway.

Andreassen et al BMC Cancer (2016) 16:799 DOI 10.1186/s12885-016-2832-x RESEARCH ARTICLE Open Access Incidence and Survival of urothelial carcinoma of the urinary bladder in Norway 1981-2014 B K Andreassen1*, B Aagnes4, R Gislefoss1, M Andreassen2 and R Wahlqvist3 Abstract Background: Urothelial carcinoma of the urinary bladder (UCB) is the 4th most common cancer type in men in developed countries, and tumor recurrence or progression occurs in more than half of the patients Previous studies report contradictory trends in incidence and survival over the past decades This article describes the trends of UCB incidence and survival from 1981 to 2014, including both invasive and non-invasive UCB using data from the Cancer Registry of Norway Methods: In Norway, 33,761 patients were diagnosed with UCB between 1981 and 2014 Incidence and 5-year relative survival were calculated, stratified by sex, morphology, stage, age and diagnostic period Age-period-cohort models were used to distinguish period- and cohort effects Temporal trends were summarized by calculating the average absolute annual change in incidence and relative survival allowing for breaks in this trend by incorporating a joinpoint analysis Excess mortality rate ratios (EMRR) quantify the relative risks by using a proportional excess hazard model Results: The incidence of UCB in men increased from 18.5 (1981-85) to 21.1 (1991-95) per 100 000 person-years and was rather stable thereafter (1996–2014) The incidence rates of UCB were lower in women increasing linearly from 4.7 to 6.2 over the past 34 years (p = 5.9 · 10-7) These trends could be explained by an increase of the incidence rates of non-invasive tumors Furthermore, the observed pattern seemed to represent a birth cohort effect Five-year relative survival increased annually with 0.004 in men (p = 1.3 · 10-6) and 0.003 in women (p = 4.5 · 10-6) There is a significant increase over the past 34 years in survival of UCB in both genders for local tumors but not for advanced stages Conclusions: Increasing and stable incidence trends mirror little improvement in primary and secondary prevention of UCB for more than three decades Survival proportions increased only marginally Thus, any changes in treatment and follow-up care did not lead to notable improvement with respect to survival of the patients High estimates of preventable cases together with large recurrence rates of this particular cancer type, demand more research on prevention guidelines, diagnostic tools and treatment for UCB Keywords: Urothelial carcinoma of the urinary bladder, Bladder cancer, Incidence, Relative survival, Trends, Registry data, Epidemiology * Correspondence: b.k.andreassen@kreftregisteret.no Department of Research, Cancer Registry of Norway, Institute for Population-based Research, Oslo, Norway Full list of author information is available at the end of the article © 2016 The Author(s) Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated Andreassen et al BMC Cancer (2016) 16:799 Background Despite large global differences in the incidence of urothelial carcinoma of the urinary bladder (UCB), this cancer type remains the second most common genitourinary malignancy after prostate cancer in men worldwide Globally, about 330 000 new UCB cases were diagnosed and 123 000 UCB patients died from the disease in 2012 UCB is most frequent in Europe, Northern America, Western Asia and Northern Africa and least common in Eastern, Western and Middle Africa, Central America and the non-western regions of Asia [1] Within Europe, UCB is the fourth most common cancer type in men with an age-standardized incidence rate (world) of 17.7 per 100 000 person-years [1] The corresponding rate in Norway is 20.8 per 100 000 personyears based on the diagnosis period from 2009 to 2013 [2] UCB incidence in women is much lower with 3.5 cases per 100 000 person-years in Europe and 6.4 in Norway International variation in UCB incidence have recently been described in detail [3], also including trends over time Several risk factors have been identified for UCB, tobacco smoking being the most predominant one The population attributable risk for ever smoking has lately been estimated to be approximately 50 % in both men and women in the US [4] and nearly 40 % in the UK [5] Men are more likely to get UCB with a male to female ratio of 3.2 in Norway [2] UCB is also related to occupational exposure to certain chemicals like aromatic amines, chlorinated hydrocarbons and polycyclic aromatic hydrocarbons [6, 7] Patients previously irradiated for pelvic and abdominal malignancies are also at increased risk, as is also shown for intake of certain drugs used in previous cancer treatment [8] as well as diabetes medication [9] UCB rarely occurs before the age of 40, and has a median age of diagnosis at 75 in the UK [10] In Norway, 95 % of all UCB cases are of the transitional cell type, and about 60 % are primarily diagnosed without invasion into subepithelial connective tissue (tumor stage T1) or muscle (T2-4) These non-invasive tumors (papillary: Ta, Carcinoma in situ: Tis) and dysplasia are characterized by its high recurrence rates after transurethral resection of an initial tumor Non-invasive papillary (Ta) tumors form the largest group and account for half of all diagnosed urothelial carcinomas The majority of these tumors will recur, but the risk of progression to invasive UCB is low (4–7 %) for lowgrade Ta tumors and approximately 12–23 % for highgrade Ta tumors [11, 12] Carcinoma in situ seems to be more likely to progress than non-invasive papillary tumors, especially if concurrent with papillary tumors [12, 13] The high recurrence rates and the low but imminent progression risk leads to a tight follow-up of the patients with frequent visits and resource demanding Page of 11 treatment as well This makes UCB one of the most expensive cancers to treat on a per-patient basis [14] in addition to being bothersome for the patients Incidence and survival trends for UCB in different countries based on cancer registry data have been described previously [15–17] However, inclusion and exclusion criteria differ with respect to diagnose groups and periods as well as classification and registration practices Furthermore, to our knowledge, none of the articles addressing UCB trends used a nationwide registry We will describe the trends of UCB incidence and survival over time in Norway for all patients diagnosed with urothelial carcinoma of the urinary bladder between 1981 and 2014, including both invasive and noninvasive UCB (including dysplasia) using data from the Cancer Registry of Norway Methods Material The Cancer Registry of Norway has since 1953, compulsory by law, registered virtually all new cancer diagnoses in Norway The registry receives information from three independent sources (clinicians, pathology laboratories, and from the Cause of Death Registry), which ensures completeness and high quality data [18] Patients are identified through the unique national personal identification number assigned to all newborns and residents in Norway since 1960 The present study comprises all new cases of histologically verified invasive and non-invasive urothelial carcinoma of the urinary bladder in the Norwegian population diagnosed between 1981 and 2014 UCB cases were selected based on morphological codes for the transitional cell type as presented in Table UCB patients diagnosed before 1981 were excluded due to registration changes in the seventies mainly for non-invasive tumors Thus, in total, 33,761 UCB patients were included in this study (Table 1) Participants were followed until death, migration or end of follow up on the 31st of March 2016 The total follow-up time was 230 783 person-years with a median follow-up time of 15.0 years Out of all 33,761 UCB patients included in this study, 228 individuals died from UCB according to the cause of death certificate Information on morphology, stage, grade, sex, age at diagnosis and date of diagnosis were retrieved from the Cancer Registry of Norway Morphology, stage and grade were defined based on the most severe diagnosis within a 5-month window including the first of the month when the first UCB diagnosis was received We define five morphology groups based on the available tumor categories and grade information: Non-invasive papillary carcinoma low- and high-grade (Ta), non-invasive flat carcinoma (Tis), dysplasia (low-grade flat carcinoma) and Andreassen et al BMC Cancer (2016) 16:799 Page of 11 Table Patient inclusion criteria Morphology code Description Morphology group 8130 Papillary, mild dysplasia, non-invasive (WHO-grade I) Non-inv pap carcinoma LG 6752 20.0 % 8131 Papillary, moderate dysplasia, non-invasive (WHO-grade II) Non-inv pap carcinoma LG 7644 22.6 % 8136 Papillary, not otherwise specified (NOS), non-invasive Non-inv pap carcinoma LG 238 0.7 % 8132 Papillary, non-invasive, high-grade (WHO-grade III) Non-inv pap carcinoma HG 2400 7.1 % 8120 Non-papillary, mild dysplasia, non-invasive (WHO-grade I) Dysplasia 303 0.9 % 8121 Non-papillary, moderate dysplasia, non-invasive (WHO-grade II) Dysplasia 589 1.7 % 8126 Non-papillary, NOS, non-invasive Dysplasia 8122 Non-papillary, non-invasive, high-grade (WHO-grade III) Carcinoma in situ 8123 Non-papillary, NOS, invasive 8124 Non-papillary, mild dysplasia, invasive (WHO-grade I) 8125 Non-papillary,moderate dysplasia, invasive (WHO-grade II) Inv carcinoma 758 2.2 % 8127 Non-papillary, invasive, high-grade (WHO-grade III) Inv carcinoma 3471 10.3 % 8133 Papillary, NOS, invasive Inv carcinoma 169 0.5 % 8134 Papillary, mild dysplasia, invasive (WHO-grade I) Inv carcinoma 237 0.7 % 8135 Papillary, moderate dysplasia, invasive (WHO-grade II) Inv carcinoma 2205 6.5 % 8137 Papillary, invasive, high-grade (WHO-grade III) Inv carcinoma 3304 9.8 % 80103a Carcinoma in situ, NOS Inv carcinoma 185 0.5 % 80203a Carcinoma, undifferentiated, invasive, NOS Inv carcinoma 91 0.3 % a Number of individuals Percentage 441 1.3 % 1198 3.5 % Inv carcinoma 319 0.9 % Inv carcinoma 28 0.1 % 812031 Highly differentiated, invasive, G1, low-grade Inv carcinoma 84 0.2 % 812032a Moderately differentiated, invasive, G2, low-grade Inv carcinoma 193 0.6 % 812033a Poorly differentiated, invasive, G3, high-grade Inv carcinoma 2180 6.5 % 812034a Undifferentiated, invasive, G4, high-grade Inv carcinoma 27 0.1 % 812039a NOS, invasive 945 2.8 % Inv carcinoma Total number of individuals 33761 Morphology codes (MOTNAC: Manual of Tumor Nomenclature and Coding from 1951 from the American Cancer Society), description, morphology groups and corresponding number and percentage of individuals included in this study a ICD-O: International Classification of Diseases for Oncology 1976- invasive carcinoma (T1-T4) Grade information is based on WHO 1973 [19] and grouped into low (LG, WHO grade and 2)- and high-grade (HG, WHO grade 3) (see Table 1) Stage is categorizsed as localized (non-invasive/ invasive cancer without any metastases), regional advanced (any infiltration into surrounding areas or regional metastases) and distant advanced (distant metastases) tumors For the presentation of the results, age at diagnosis was divided into four age groups (≤49, 50–64, 65–79, ≥80) The year of diagnosis is grouped into 5-years intervals (diagnostic periods): 1981–1985, 1986–1990, …, 2006–2010 and 2011–2014 Statistics Incidence rates (per 100 000 person-years) were calculated based on the number of individuals getting their first UCB diagnosis and the number of individuals living in Norway for a certain sex, diagnostic time-period and age group Age-specific incidence rates are presented for each of the four age-groups stratified for sex Direct agestandardized incidence rates were calculated applying the World Standard Population [20] according to sex as well as age group, morphology group and stage across all diagnostic periods Temporal trends of the incidence rates were best represented by a linear model, where the estimated regression coefficient β^I represents the average absolute annual incidence change In order to summarize the observed trend over the last 34 years, this parameter has been provided together with the standard error and p-values for the test of an incidence change over time We also implemented a joinpoint analysis [21] to uncover trends, which change over time In order to interpret trends in age-specific incidence rates over time, we also apply an extension of the age-periodcohort model [22] to separate diagnosis period and birth cohort effects An APC model incorporating restricted cubic splines, implemented in Stata was used [23, 24] The APC model was applied for male patients with an Andreassen et al BMC Cancer (2016) 16:799 age at diagnosis between 70 and 80, diagnosed between 1981 and 2010 and born between 1910 and 1930, which means that the model includes reliable information from the birth cohorts of interest 5-year relative survival, based on the cohort approach, was estimated using the age-standardardized Ederer II method applying national population lifetables by sex, age group and diagnosis period [25] The internal age-standardization used the age distribution of the last diagnostic period 2011-14 as weights Temporal trends of 5-year relative survival rates were best represented by a linear model Thus, the average absolute change in annual 5-year relative survival estimates was provided together with the standard error and p-values for the test of a significant trend We also implemented a joinpoint analysis [21] to uncover those trends, which change over time The annual change in 5-year survival proportions was estimated by the regression coefficient β^ RS : Because follow-up data for the latest diagnostic period are lacking, 5-year survival estimates for 2011-14 are based on a period approach The corresponding column is marked with an (*) in order to emphasize the differently derived estimates and these estimates have not been included in the trend analysis We fitted a proportional excess hazard model [26–28] where sex, diagnostic period, age group, morphology group and stage were included as categorical variables The baseline hazard was modelled using 5df for the spline variables using the Stata command stpm2 [29] Excess mortality rates estimate the absolute difference between the expected mortality rate (from lifetables) and the observed mortality rate (from the data) The ratio of these quantities, the excess mortality rate ratios (EMRR), are in their interpretation similar to the hazard rate ratio and thus represent the factor of which patients under a certain condition are more likely to die compared to patients under another condition EMRRs are reported together with 95 % confidence intervals (CI) All statistical analyses were performed in Stata 14/MP for Windows [30] Page of 11 Table Patient characteristics Men Women All % 75.6 24.4 100.0 Age [25–75 % percentile] 72 [64–79] 73 [65–81] 72 [64–79] Non-inv pap trans carcinoma low-grade 43.4 43.0 43.4 Non-inv pap trans carcinoma high-grade 7.6 5.6 7.1 Displasia 3.9 4.1 3.9 Carcinoma in situ 3.7 3.1 3.6 41.3 44.3 42.0 Morphology Inv trans carcinoma Stage Localised 91.5 89.9 91.1 Regional advanced 5.6 5.9 5.7 Distant advanced 2.9 4.1 3.2 Bladder cancer 15.0 17.2 15.5 Other cancer 22.1 21.4 22.0 Other than cancer 30.2 26.2 29.1 2.7 2.6 2.8 30.0 32.6 30.6 Death Unknown Alive Distribution of age, morphology group, stage and cause of death by sex and in total in the study population of patients diagnosed with urothelial carcinoma of the urinary bladder in Norway from 1981 to 2014 were diagnosed with non-invasive papillary carcinoma Ta (43.4 % low-grade, 7.1 % high-grade) Invasive transitional carcinoma (T1-T4) accounted for 42.0 % of all UCB cases in this study and carcinoma in situ (3.6 %) as well as dysplasia (3.9 %) are the least frequent morphology groups Out of all patients diagnosed between 1981 and 2014, 66.6 % had died by 31st of March 2016, either due to UCB (15.5 %), cancer (not UCB) (22.0 %) or causes other than cancer (29.1 %) Women had relatively more invasive (44.3 vs 41.3 %) and more advanced (10.0 vs 8.5 %) tumors than men Incidence Results Overview A total number of 33,761 cases was diagnosed with UCB (transitional cell type) between 1981 and 2014 An overview over these patients with respect to sex as well as vital status (UCB and other cancer related death, alive, unknown), morphology group, stage, and age by sex and combined is provided in Table Three quarters of the UCB patients diagnosed between 1981 and 2014 were men For all patients (men and women combined), the median age at diagnosis was 72 years (inter-quartile range: 64–79 years) The majority of patients (50.5 %) Age-standardized incidence rates (World) are summarized in seven diagnostic periods in Table In addition, estimates for the average annual incidence   change β^ are provided These quantities estimate the I average incidence trend throughout the study period and give an indicator for whether (and how much) incidence changed linearly over the past 34 years For men, after a slightly increasing trend in the 1980s, UCB incidence has been stable throughout the remaining study period A joinpoint analysis revealed an increasing trend of 0.34 (p = 0.048) from 1981-89 and a stable trend from 1990 to 2014 ( β^ I =0.02, p = 0.531) Thus, on average, Andreassen et al BMC Cancer (2016) 16:799 Page of 11 Table Incidence rates 1981-1985 1986-1990 1991-1995 1996-2000 2001-2005 2006-2010 2011-2014 βI (SE) Men n Women n Men p-value 2972 3321 3628 3575 3928 4192 3915 18.5 19.7 21.1 19.7 20.6 20.4 974 1038 1110 1150 1262 1380 4.7 4.9 5.2 5.1 5.3 5.7 6.2 0.043(0.007) 5.9E-07a 2.0 1.8 2.1 2.0 1.9 1.8 2.5 0.008(0.007) 0.246 21.4 0.070(0.021) 0.002a 1316 Age (years) 0–49 44.4 −0.196(0.102) 0.065 50–64 46.2 49.0 50.4 40.3 42.4 42.6 65–79 148.4 156.0 171.0 169.1 175.4 176.1 173.1 0.899(0.186) 3.2E-05a 80+ 194.1 256.2 263.1 268.0 301.8 286.1 317.8 3.47(0.45) 7.1E-09a Non-inv pap carcinoma LG 8.7 9.5 9.9 9.2 9.5 8.9 8.3 −0.016(0.016) 0.335 Non-inv pap carcinoma HG 0.6 0.9 1.3 0.9 1.4 2.3 2.6 0.061(0.006) 1.5E-10a Dysplasia 0.6 0.7 1.0 0.9 0.6 0.6 1.4 0.011(0.006) 0.070 Carcinoma in situ 0.4 0.7 0.7 0.9 0.9 0.9 0.7 0.013(0.003) 0.002a Inv carcinoma 8.2 8.0 8.2 7.8 8.2 7.7 8.4 −0.001(0.010) 0.985 16.6 17.9 19.6 18.2 18.6 18.5 19.9 0.072(0.021) 0.001a Regional advanced 1.3 1.1 1.0 0.8 1.3 1.4 1.0 0.001(0.005) 0.919 Distant advanced 0.6 0.7 0.5 0.7 0.7 0.6 0.4 −0.003(0.003) 0.380 Morphology Stage Localised Women Age (years) 0–49 0.7 0.7 0.8 0.7 0.6 0.7 0.8 0.001(0.004) 0.739 50–64 12.3 13.0 12.8 11.6 13.8 14.1 15.0 0.083(0.034) 0.021a 65–79 34.2 35.7 39.2 41.3 41.2 44.8 47.5 0.425(0.061) 6.4E-08a 80+ 57.0 52.9 50.8 52.3 61.2 61.4 76.3 0.519(0.167) 0.004a Non-inv pap carcinoma LG 2.1 2.4 2.4 2.5 2.8 2.8 2.6 0.022(0.005) 1.0E-04a Non-inv pap carcinoma HG 0.1 0.1 0.3 0.2 0.2 0.4 0.6 0.014(0.002) 5.4E-08a Dysplasia 0.2 0.2 0.2 0.2 0.2 0.2 0.6 0.006(0.003) 0.037a 0.233 Morphology Carcinoma in situ 0.1 0.2 0.1 0.2 0.2 0.2 0.1 0.002(0.001) Inv carcinoma 2.3 2.0 2.2 1.9 2.0 2.1 2.3 −0.001(0.005) 0.823 Localised 4.2 4.4 4.7 4.5 4.7 5.0 5.7 0.040(0.008) 8.6E-06a Regional advanced 0.4 0.3 0.2 0.3 0.4 0.4 0.3 0.001(0.001) 0.611 Distant advanced 0.2 0.2 0.2 0.2 0.2 0.3 0.2 0.002(0.001) 0.172 Stage Age-standardized incidence rates (applying the World Standard Population) by sex, morphology group and stage as well as age-specific incidence rates stratified   for 5-years interval of diagnosis from 1981 to 2014 Average annual incidence changes β^ I are reported together with standard error (SE) and the p-value for the test of a significant incidence trend Significant p-values (based on the % threshold) are marked witha the incidence increased by 0.34   β^ I within a year or 2.7 from 1981 to 1989 The remaining 26 years of the study period, the incidence increased on average 0.02 per year or 0.5 from 1990 to 2014 The incidence of UCB in men was between 18.3 and 21.4 per 100 000 person-years for all diagnostic periods during the study period The incidence of UCB was lower in women with incidence rates increasing from 4.7 to 6.2 over the past 34 years The corresponding trend was significant: β^ I = 0.043 (p = 5.9 · 10-7) In men, age-specific incidence rates were increasing during the past 34 years, especially for the oldest patients (β^ = 3.5, p = 7.1 · 10-9) and those between 65 and 79 (β^ = I I 0.9, p = 3.2 · 10-5) Similar age-dependent incidence trends could also be seen in women, although less pronounced probably due to the lower number of cases This observed Andreassen et al BMC Cancer (2016) 16:799 pattern was most likely mainly due to a birth cohort effect as illustrated in Fig The APC model confirmed the ageeffect (Fig 1a) and suggested a larger birth cohort effect compared to the diagnosis period effect (Fig 1b) The incidence rate ratio (IRR) was 1.22 (CI: 1.04–1.45) when comparing the 1930 birth cohort to the one from 1910 This particular birth cohort effect stayed the same when reducing the model to an age-cohort model (results not shown) In men, there was a significant increase in high-grade non-invasive papillary carcinoma (Ta HG: p = 1.5 · 10-10) over the study period Age-standardized incidence rates in men have been rather stable over the whole observation period for invasive carcinoma (p = 0.985) and lowgrade non-invasive papillary carcinoma (Ta LG p = 0.335) The incidence of both high- and low-grade noninvasive papillary carcinoma (Ta) was increasing in women (HG p = 5.4 · 10-8, LG p = 1.0 · 10-4) The corresponding increase of incidence rates for carcinoma in situ has been less pronounced in women (p = 0.233), possibly due to small numbers of cases A joinpoint Page of 11 analysis reveals that the increase in incidence rates of high-grade non-invasive papillary carcinoma is rather small until 2001 (men: p = 0.055) and 2003 (women: p = 0.105), but significant thereafter (men: p = 1.0 · 10-8, women: men: p = 1.0 · 10-8) Both genders showed an increasing trend with respect to the incidence rates for localized cancers This trend was more pronounced for women (p = 8.6 · 10-6) than men (p = 0.001) Cases with advanced stage were rather rare, such that the interpretation suffered from small number of cases in both men and women Still, there is a decreasing tendency for distant advanced tumors in men (p = 0.380), while the corresponding tendency in women is increasing (p = 0.172) Relative Survival Table presents the sex-specific 5-year relative survival across 5-year diagnosis intervals from 1981 to 2014 stratified for age and morphology group as well as stage   Furthermore, the average annual survival change β^ RS estimates the average trend of the 5-year relative survival Fig Age-standardized incidence rates per 100 000 person-years (a) and incidence rate ratios for birth cohort and diagnostic period effects for men diagnosed with urothelial carcinoma of the urinary bladder in Norway (b) 1996-2000 2001-05 2011-14a βRS (SE) p-value Men 0.67 (0.64,0.70) 0.71 (0.68,0.74) 0.73 (0.70,0.76) 0.72 (0.70,0.75) 0.75 (0.72,0.77) 0.77 (0.75,0.79) 0.77 (0.75,0.79) 0.004 (0.001) 1.3E-06b Women 0.63 (0.59,0.67) 0.68 (0.64,0.72) 0.65 (0.61,0.69) 0.70 (0.67,0.74) 0.70 (0.67,0.73) 0.72 (0.69,0.75) 0.74 (0.71,0.77) 0.003 (0.001) 4.5E-06b 0–49 0.90 (0.84,0.95) 0.85 (0.78,0.90) 0.93 (0.88,0.97) 0.92 (0.86,0.95) 0.89 (0.83,0.93) 0.91 (0.85,0.95) 0.94 (0.84,0.98) 0.001 (0.001) 0.623 50–64 0.78 (0.74,0.81) 0.81 (0.78,0.85) 0.83 (0.80,0.86) 0.84 (0.80,0.87) 0.84 (0.81,0.86) 0.83 (0.81,0.86) 0.89 (0.85,0.91) 0.003 (0.001) 0.006b 65–79 0.69 (0.65,0.72) 0.68 (0.65,0.72) 0.72 (0.70,0.75) 0.73 (0.70,0.76) 0.75 (0.72,0.78) 0.78 (0.76,0.81) 0.78 (0.73,0.81) 0.005 (0.001) 7.6E-07b 80+ 0.53 (0.45,0.63) 0.65 (0.57,0.73) 0.63 (0.56,0.71) 0.60 (0.53,0.66) 0.64 (0.58,0.70) 0.68 (0.62,0.73) 0.63 (0.54,0.72) 0.007 (0.003) 0.015b Non-inv pap carcinoma LG 0.85 (0.79,0.89) 0.92 (0.87,0.95) 0.91 (0.87,0.95) 0.93 (0.88,0.96) 0.91 (0.87,0.94) 0.94 (0.90,0.97) 0.93 (0.84,0.97) 0.003 (0.001) 0.001b Non-inv pap carcinoma HG 0.94 (0.18,1.00) 0.76 (0.63,0.85) 0.84 (0.71,0.92) 0.80 (0.66,0.88) 0.82 (0.72,0.88) 0.87 (0.80,0.92) 0.88 (0.77,0.94) 0.004 (0.002) 0.050 Dysplasia 0.76 (0.56,0.87) 0.63 (0.47,0.76) 0.76 (0.61,0.86) 0.83 (0.68,0.92) 0.85 (0.67,0.93) 0.83 (0.66,0.92) 0.74 (0.54,0.86) 0.004 (0.003) 0.155 Carcinoma in situ 0.79 (0.45,0.93) 0.62 (0.48,0.74) 0.64 (0.51,0.75) 0.64 (0.53,0.73) 0.84 (0.69,0.92) 0.83 (0.71,0.90) 0.91 (0.70,0.97) 0.013 (0.004) 1.6E-04b Inv carcinoma 0.47 (0.43,0.51) 0.49 (0.45,0.52) 0.51 (0.48,0.55) 0.50 (0.47,0.54) 0.54 (0.50,0.57) 0.55 (0.52,0.58) 0.58 (0.54,0.63) 0.003 (0.001) 2.3E-04b Localised 0.73 (0.69,0.76) 0.76 (0.73,0.79) 0.77 (0.74,0.79) 0.77 (0.74,0.79) 0.80 (0.78,0.82) 0.82 (0.80,0.84) 0.81 (0.77,0.84) 0.004 (0.001) 7.0E-06b Regional advanced 0.25 (0.17,0.34) 0.27 (0.20,0.36) 0.28 (0.19,0.38) 0.23 (0.15,0.31) 0.25 (0.18,0.32) 0.27 (0.21,0.33) 0.22 (0.04,0.49)